Schwann Cell Protein Kinase RNA-like ER Kinase (PERK) Is Not Necessary for the Development of Diabetic Peripheral Neuropathy but Negates the Efficacy of Cemdomespib Therapy

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes arising in part from glycemic damage to neurons and Schwann cells (SC). While the pathogenic mechanisms of DPN are complex, mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to the development of DPN and serve as therapeutic targets for disease modification. Cemdomespib is an orally bioavailable small molecule which alleviates clinical indices of DPN that correlate with improvements in neuronal oxidative stress and mitochondrial bioenergetics. However, the contribution of SC ER stress in the onset of DPN and the therapeutic efficacy of cemdomespib remains unknown. To address this issue, mice expressing a conditional deletion of protein kinase RNA-like ER kinase (PERK) in myelinating SCs (SC-cPERK KO) and control SC-PERK^f/f mice were rendered diabetic with streptozotocin. Diabetic SC-PERK^f/f and SC-cPERK KO mice developed a similar magnitude of DPN as quantified by the onset of a thermal/mechanical hypoalgesia, decreases in nerve conduction velocity (NCV) and intraepidermal fiber density (iENFD). After 8 weeks of diabetes, daily treatment with 1 mg/kg cemdomespib for an additional 8 weeks significantly improved thermal/mechanical hypoalgesia, NCV, iENFD and decreased markers of ER stress in diabetic SC-PERK^f/f mice, but the drug had no effect in diabetic SC-cPERK KO mice. Nrf2 is a PERK substrate and studies using rat SCs subjected to ER stress demonstrated that cemdomespib increased Nrf2 activity. Collectively, these data suggest that activation of SC PERK by diabetes is not necessary for the onset of DPN, but serves as a target in the action of cemdomespib, potentially by increasing Nrf2 activity.